The burden of chronic viral infections worldwide is extraordinarily high, with HIV-1 and HCV foremost causes of morbidity and mortality. Through a variety of immune evasion mechanisms these pathogens establish long-term chronic viremia in their infected hosts, leading to immune destruction in the case of HIV-1 and liver disease and hepatocellular carcinoma in the case of HCV. On the other hand, it is not clear why a significant portion of persons infected with these viruses are able to spontaneously control these infections and avoid their complications. Mechanisms underlying control of HCV and HIV-1 remain incompletely understood but have enormous implications for development of successful therapeutic approaches. There is already evidence for a genetic basis of spontaneous control of each of these viruses. Genome wide association surveys and other novel fine mapping scans of immune loci such as HLA will identify more genes contributing to spontaneous HCV clearance. Subsequent translation of genotype into phenotype using functional assays for HCV clearance will put these findings into biological context. HCV and HIV-1 controller datasets allow us a unique opportunity to identify genetic associations favorable to the control of either or both viruses. The goal of this proposal is to assess novel host genetic associations with HCV control and to elucidate their underlying mechanisms. In Aim 1, we will leverage a GWAS of HCV spontaneous clearance. With our collaborators at the Broad Institute, we will perform a novel, high-throughput ImmunoChip scan that fine maps key immune and inflammatory loci postulated to be involved in autoimmune diseases including HLA loci. Building large tissue and PBMC banks will facilitate validation and functional studies. Studies proposed in Aim 2 exploit the existence of two unique controller datasets (HCV and HIV-1) using cross-disease analysis to determine whether there are unappreciated loci common to control of both infections. We will then confirm polymorphisms common to the control of both infections by examining a unique cohort of dual controllers, co- infected persons who controlled both infections. Because of the PIs' collective expertise in innate and adaptive immunity, we are well poised to translate our findings into functional studies involving hepatocyte-based models (Aim 3), and PBMCs (via links to other projects and collaborations). We will leverage a large network of injection drug user cohorts that includes incident or acute HCV cases, many with the capacity to rapidly translate genetic findings into functional experiments.